Merkel Cell Carcinoma (MCC) is a skin cancer that is thought to arise from the uncontrolled growth of so-called Merkel cells, which serve as mechanoreceptors and osmoreceptors essential for light-touch response. MCC incidence is about 1,500 US cases per year, and this number is continually increasing. MCC is an aggressive cancer type, highly metastatic, and it is only cured when detected early. Critical issues in the field are to better understand the mechanisms of MCC development to be able to detect this deadly cancer earlier and to treat patients more effectively. Such issues are extremely challenging to address in human patients due to limitations in acquiring and studying tumor samples from these patients and also because many cases of MCC are detected late in the course of the disease. The exact cause of MCC is still unclear, but its development may be linked to sun exposure and immunosuppression. MCC development also correlates very strongly with infection by MCPyV (Merkel Cell PolyomaVirus), a virus that was first described in 2008. The current model is that, in many cases of MCC, cellular or organism stress creates a favorable environment for activation of the MCPyV genome, resulting in the induction of proliferation and cancer initiation. Based on virology studies with other polyomaviruses in various species and recent data in MCC primary tumors and cell lines, we hypothesize that inhibition of the RB and p53 tumor suppressor pathways is critical in the early stages of MCC development. Our first aim is to test this hypothesis by deleting Rb family genes and p53 in Merkel cells in the skin of mice using advanced tools of mouse genetics. We also hypothesize that MCC initiation correlates with changes in transcriptional profiles in Merkel cells, in part because of inactivation of the RB and p53 transcriptional regulators. Our second specific aim is to examine changes in gene expression in Merkel cells upon loss of function of RB and p53 function; to detect these changes; we will use novel high-throughput RNA sequencing methods. If successful, these experiments will provide the first pre-clinical model of Merkel Cell Carcinoma and will identify novel candidate biomarkers and potential therapeutic targets to detect and treat patients.